Telacebec (Q203) is a potent drug candidate under clinical development for the treatment of drug-naïve and drug-resistant tuberculosis. The first-in-human randomized, placebo-controlled, double-blind, dose-escalation Phase 1A trial (Q203-TB-PI-US001) was conducted to evaluate the safety, tolerability, and pharmacokinetics of telacebec. A total of 56 normal, healthy, male and female subjects (42 active and 14 placebo) were enrolled in the study. The doses of telacebec were 10 mg (Cohort 1), 30 mg (Cohort 2), 50 mg (Cohort 3), 100 mg (Cohort 4), 200 mg (Cohort 5), 400 mg (Cohort 6), and 800 mg (Cohort 7) in a fasted state. Subjects participating in Cohort 4 were also enrolled in Cohort 8 to investigate the food effect on the pharmacokinetics of telacebec after a high-fat meal. In all subjects dosed with telacebec (10 – 800 mg), telacebec was well tolerated and did not lead to any significant or serious adverse events. Following a single oral administration of telacebec (10 – 800 mg), telacebec plasma concentration reached the maximal plasma concentration (C max ) in average 2.0 – 3.5 h and showed multi-exponential decline thereafter. The area under the plasma concentration vs. time curve (AUC) was approximately dose-proportional. A significant increase in plasma concentrations was observed in the fed condition compared with the fasted condition with the geometric mean ratio of 3.93 for C max . Moderate delay in T max (4.5 h) was also observed in the fed condition. These results, combined with the demonstrated activity against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis , support further investigation of telacebec for the treatment of tuberculosis.

Cyclin-dependent kinase 7 (CDK7) a member of the cyclin-dependent kinase family, forms a functional CDK-activating kinase (CAK) with cyclin H and MAT1, which regulates the cell cycle by phosphorylating other CDKs. CDK7 is also a component of transcription factor II H (TFIIH) that regulates transcriptional initiation and elongation through the phosphorylation of the RNA polymerase II C-terminal domain (CTD). Inhibition of CDK7 has been reported as a potential cancer therapeutic by addressing aberrant cell cycle regulation and transcription, as these abnormalities are considered main factors for tumor progression in specific types of cancer. Q901 is a novel highly selective CDK7 inhibitor in IND enabling development stage. Q901 shows extreme selectivity by singular inhibition of CDK7 among tested kinome panel. Q901 triggers G1 cell cycle arrest in specific cancer models in vitro and in vivo. Good correlation has been demonstrated between Q901 tumor growth inhibition and target engagement of a pharmacodynamics marker in treated models, suggesting CDK7 is a main driver of tumor progression in the selected models. The Q901 data supports the continued preclinical evaluation and potential of the compound as investigational treatment for patients with multiple solid tumors. Citation Format: Donghoon Yu, Yeejin Jeon, Dongsik Park, Mooyoung Seo, Wongyun Ahn, Jaeseung Kim, Choa Park, Euna Jeong, Sukjoon Yoon, Kiyean Nam. Development of highly selective CDK7 inhibitor Q901 for solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4855.

Functional composition of tumor micro-environment (TME) has been regarded as one of the most important factors in tumor progression. Cancer cells induce immune suppressive condition in TME in order to evade immune system as well as to promote metastasis. Axl, Mer and CSF1R play important roles in making tumor friendly TME by increasing regulatory T cells (Tregs), M2 macrophages, myeloid-derived suppression cells (MDSCs) and suppressing antigen presentation. On the other hand, in cancer cells, overexpression of Axl is reported to have correlation with poor prognosis of patients through promoting epithelial-to-mesenchymal transition (EMT) and inducing drug resistance to chemo or targeted therapy. Q702 is an orally available selective Axl, Mer and CSF1R triple kinase inhibitor under IND enabling studies. In this poster, we present dual potentials of Q702 leading to tumor regression through: 1) immune stimulating activities of Q702 through decreasing Tregs, M2 macrophages, MDSCs population and promoting antigen presentation, 2) direct cytotoxic activity in tumor models including acute myeloid leukemia (AML) and EGFR TKI resistant non-small cell lung cancer (NSCLC). Citation Format: Yeong-In Yang, Hwankyu Kang, Dongsik Park, Yeejin Jeon, Jeongjun Kim, Baejung Choi, Jaeseung Kim, Jinkyung Rho, Jaecheol Lee, Kiyean Nam. Q702, selective Axl, Mer and CSF1R triple kinase inhibitor with dual potentials leading to tumor regression: Immuno-oncology therapy and targeted cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4139.

CDK4/6 inhibitors, in combination with hormone therapy, has made a breakthrough in treatment of hormone receptor-positive, HER2-negative metastatic breast cancers. However, in clinical practice, a substantial number of patients who responded to CDK4/6 inhibitors eventually develop resistance within 2-3 years. Current knowledge of the molecular mechanisms of CDK4/6 inhibitor resistance is under investigation , with the loss of function of the retinoblastoma (RB) protein the most frequently observed change in resistance to CDK4/6 inhibitors. RB loss of function by CDK4/6 inhibitors appears an irreversible mechanism of resistance while gain of cyclin E, and overexpression of CDK2 reducing cyclin D1-CDK4/6 dependency which results in the resistant cell to re-enter into s-phase. Thus, inhibition of the cyclin E-CDK2 axis may be effective in overcoming resistance to CDK4/6 inhibitors. We report a novel treatment strategy that targets Cyclin-dependent kinase 7 (CDK7) in CDK4/6 inhibitor-resistant, ER+ breast cancer. Q901 is a novel highly-selective inhibitor against CDK7 and demonstrates good functional inhibition of CDK activating kinase (CAK) activities leading to activation of CDK4, 6 and CDK2 in vitro and in vivo. Q901, monotherapy, effectively inhibited tumor growth in ER+ breast cancer xenograft model as well as CDK4/6 inhibitor resistant PDX model. The results suggest a potential for Q901 in treatment of hormone receptor-positive, HER2-negative metastatic breast cancer, regardless of resistance status to CDK4/6 inhibitors. Citation Format: Donghoon Yu, Yeejin Jeon, Dongsik Park, Mooyoung Seo, Wongyun Ahn, Jaeseung Kim, Kiyean Nam. Q901, a selective CDK7 inhibitor, a potential new strategy for primary and CDK4/6 inhibitor resistant ER-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1953.